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. 1995 Aug;96(2):1059–1065. doi: 10.1172/JCI118092

Natriuretic peptides inhibit angiotensin II-induced proliferation of rat cardiac fibroblasts by blocking endothelin-1 gene expression.

H Fujisaki 1, H Ito 1, Y Hirata 1, M Tanaka 1, M Hata 1, M Lin 1, S Adachi 1, H Akimoto 1, F Marumo 1, M Hiroe 1
PMCID: PMC185295  PMID: 7635942

Abstract

The present study was aimed to test the role of endothelin-1 (ET-1) as a possible autocrine/paracrine growth factor for cardiac fibroblasts, and to examine its interaction with cardiac natriuretic hormones. Expression of preproET-1 (ppET-1) mRNA by cultured cardiac fibroblasts from neonatal rats was demonstrated by Northern blot analysis using cDNA for rat ppET-1 as a probe. Angiotensin II (ANG II) and ET-1 transiently (30 min) increased steady-state ppET-1 mRNA levels in cardiac fibroblasts. Both ET-1 and ANG II significantly stimulated [3H] thymidine incorporation into cardiac fibroblasts, whose effects were dose-dependently inhibited by an ETA receptor antagonist (BQ123), BQ123 also inhibited both ET-1- and ANG II-induced ppET-1 mRNA expression. Both atrial and brain natriuretic peptides (ANP, BNP), which activate particulate guanylate cyclase, inhibited ppET-1 mRNA expression and [3H]thymidine incorporation stimulated by ANG II and ET-1. Sodium nitroprusside, a soluble guanylate cyclase activator, and 8-bromocyclic GMP, a membrane-permeable cGMP derivative, similarly inhibited ppET-1 mRNA expression and [3H]-thymidine incorporation. BNP was more potent than ANP to inhibit ANG II- and ET-1-stimulated DNA synthesis, whereas BNP and ANP were almost equipotent in stimulating cGMP generation in cardiac fibroblasts. Our data demonstrated that ANG II and ET-1 upregulate ET-1 gene expression in rat cardiac fibroblasts partly via cyclic GMP-dependent mechanism, and that natriuretic peptides inhibit ANG II-stimulated proliferation of cardiac fibroblasts, possibly by inhibiting ET-1 gene expression. Our data suggest the possible role of endogenous ET-1 as an autocrine/paracrine growth factor for cardiac fibroblasts and its close interaction with natriuretic peptides in the regulation of cardiac fibrosis.

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